Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis.

IF 2.5 4区 医学 Q3 CHEMISTRY, MEDICINAL
Yuebiao Zhou, Ignacio Aliagas, Shumei Wang, Chun Sing Li, Zhiguo Liu, Christine M Bowman, Daniel J Burdick, Kevin R Clark, Tahnee J Dening, John Flygare, Anjani Ganti, Hany S Girgis, Emily J Hanan, Seth F Harris, Chloe Hu, Sharookh B Kapadia, Michael F T Koehler, Tommy Lai, Jun Liang, Xingrong Liu, Fang Ma, Jialin Mao, Jeremy Nicolai, Jessica Sims, Savita Unhayaker, John Wai, Xiaojing Wang, Ping Wu, Yiming Xu, Chun-Wan Yen, Renwei Zhang, Torben F Elfert, Man-Wah Tan, Eric M Kofoed, Terry D Crawford
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引用次数: 0

Abstract

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5'-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and ADME profiles.

发现用于治疗结核病的 GuaB 强效二氢噁嗪喹啉酮抑制剂。
结核病是由结核分枝杆菌(M.tb)引起的传染病,是导致死亡的主要原因。全世界有超过 10 亿人被认为感染了结核分枝杆菌。作为目前治疗标准的多种药物疗法需要至少四个月的用药时间,而耐药结核分枝杆菌的治疗疗程要长得多。肌苷-5'-单磷酸脱氢酶(GuaB)是进行鸟嘌呤核苷酸新生物合成的限速酶,对包括结核分枝杆菌在内的细菌的生长和存活至关重要。开发一种能抑制 GuaB 的新型抗生素能以新颖的方式与现有疗法相结合,从而为治疗结核病的有效疗法做出贡献。在此,我们介绍了结构独特的小分子 GuaB 抑制剂的发现,这些抑制剂对 M.tb H37Ra 和 H37Rv 菌株有很强的抑制作用,并且具有理想的安全性和 AMDE 特性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.70
自引率
3.70%
发文量
463
审稿时长
27 days
期刊介绍: Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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